A new approach for predicting the pK(a) value for a specific residue in complex environments has been proposed. It is based on a combination of hybrid quantum mechanical/molecular mechanical (QM/MM) potential and the free energy perturbation (FEP) technique. With a specific thermodynamic cycle, the QM/MM-FEP protocol can be carried out for pK(a) predictions taking advantage of the dual-topology-single-coordinate scheme proposed earlier for performing FEP calculations with QM/MM potentials. The new method has been tested for ethanethiol (CH3CH2SH) in solution. It was shown that, although the dominant contribution is from electrostatic interactions between the solute and solvent, many other factors have to be carefully dealt with to obtain reliable pK(a) values. The contribution from van der Waals interactions associated with the dummy atom was found to be insignificant for the present case, because the solvent structure around the solute is essentially determined by the heavy atoms. With more systematic benchmark calculations, the QM/MM-FEP approach will become a useful tool for pK(a) predictions in systems such as metalloenzymes, where nontrivial electronic structural change and/or atomic structural rearrangements are expected as the protonation state of a specific residue varies.